Specific Cell Targeting by Toxoplasma gondii Displaying Functional Single-Chain Variable Fragment as a Novel Strategy; A Proof of Principle.

Toxoplasma gondii holds significant therapeutic potential; however, its nonspecific invasiveness results in off-target effects. The purpose of this study is to evaluate whether T. gondii specificity can be improved by surface display of scFv directed against dendritic cells' endocytic receptor, DEC205, and immune checkpoint PD-L1. Anti-DEC205 scFv was anchored to the T. gondii surface either directly via glycosylphosphatidylinositol (GPI) or by fusion with the SAG1 protein. Both constructs were successfully expressed, but the binding results suggested that the anti-DEC-SAG1 scFv had more reliable functionality towards recombinant DEC protein and DEC205-expressing MutuDC cells. Two anti-PD-L1 scFv constructs were developed that differed in the localization of the HA tag. Both constructs were adequately expressed, but the localization of the HA tag determined the functionality by binding to PD-L1 protein. Co-incubation of T. gondii displaying anti-PD-L1 scFv with tumor cells expressing/displaying different levels of PD-L1 showed strong binding depending on the level of available biomarker. Neutralization assays confirmed that binding was due to the specific interaction between anti-PD-L1 scFv and its ligand. A mixed-cell assay showed that T. gondii expressing anti-PD-L1 scFv predominately targets the PD-L1-positive cells, with negligible off-target binding. The recombinant RH-PD-L1-C strain showed increased killing ability on PD-L1+ tumor cell lines compared to the parental strain. Moreover, a co-culture assay of target tumor cells and effector CD8+ T cells showed that our model could inhibit PD1/PD-L1 interaction and potentiate T-cell immune response. These findings highlight surface display of antibody fragments as a promising strategy of targeting replicative T. gondii strains while minimizing nonspecific binding.

Impaired creative cognition after surgery for an IDH-mutated glioma: A proof-of-concept study.

Assessment of high cognitive functions, such as creativity, is often overlooked in medical practice. However, it is crucial to understand the impact of brain tumors, specifically low-grade gliomas, on creative cognition, as these tumors predominantly affect brain regions associated with cognitive creativity. In this study, we investigated creative cognition using the Alternative Uses Task (AUT) and the Combination of Associates Task (CAT) in a cohort of 29 patients who underwent brain surgery for a low-grade glioma, along with 27 control participants. While the group of patients did not exhibit deficits in clinical neuropsychological assessments, our results revealed significant impairment in generating original and creative ideas compared to the control group. Furthermore, when analyzing the specific brain regions affected by the tumors, patients with lesions overlapping the left rostro-lateral prefrontal cortex, a critical region for creativity, displayed more pronounced impairments in the CAT compared to patients with lesions outside this region. These findings provide proof of concept that patients can experience impaired creative cognition following surgery for low-grade glioma, highlighting the importance of assessing higher-order cognitive functions, including creativity, in neurosurgical patients. Moreover, beyond its clinical relevance, our study contributes to advancing our understanding of the neuroscience of creativity.

Verbal fluency predicts work resumption after awake surgery in low-grade glioma patients.

BACKGROUND: Resuming professional activity after awake surgery for diffuse low-grade glioma (DLGG) is an important goal, which is not reached in every patient. Cognitive deficits can occur and persist after surgery. In this study, we analyzed the impact of mild cognitive impairments on the work resumption. METHODS: Fifty-four surgeries (including five redo surgeries) performed between 2012 and 2020 for grade 2 (45) and 3 (nine) DLGG in 49 professionally active patients (mean age 40 [range 23-58.) were included. We retrospectively extracted the results of semantic and phonemic verbal fluency tests from preoperative and 4-month postoperative cognitive assessments. Patients were interviewed about their working life after surgery, between April and June 2021. RESULTS: Patients (85%) returned to work, most within 3 to 6 months. Patients (76%) reported subjective complaints (primarily fatigue). Self-reported symptoms and individual and clinical variables had no impact on the work resumption. Late-postoperative average Z-scores in verbal fluency tasks were significantly lower than preoperative for the entire cohort (Wilcoxon test, p < 0.001 for semantic and p = 0.008 for phonemic fluency). The decrease in Z-scores was significantly greater (Mann Whitney U-test, semantic, p = 0.018; phonemic, p = 0.004) in the group of patients who did not return to work than in the group of patients who did. CONCLUSION: The proportion of patients returning to work was comparable to similar studies. A decrease in verbal fluency tasks could predict the inability to return to work.

Oncological and functional outcomes support early resection of incidental IDH-mutated glioma.

PURPOSE: The main objective was to assess the neuropsychological, epileptical, and oncological outcomes in a series of patients operated on for a IDH-mutated diffuse low-grade glioma (DLGG) of incidental discovery (iDLGG). METHODS: We retrospectively reviewed a consecutive series of surgically treated adults with DLGG and selected cases incidentally discovered. Tumor volumes, growth rates, and extents of resection (EOR) were assessed by volumetric measures of fluid-attenuated inversion recovery magnetic resonance imaging. The data on oncological, functional, and epileptical results were retrieved from the patients' digital files. RESULTS: Among all patients with DLGG resected at our center between June 2011 and April 2022, we found eleven cases with an incidental discovery. Resection was supratotal, gross total, and subtotal in 45.5%, 26.4%, and 18.1% of cases, respectively. The rate of epileptic seizures after the surgery was 9.1%. There were 45.4% of patients that had tumor progressions and the overall mean time to tumor progression was 42 months. After the surgery, 3 (27.3%) patients had mild neurocognitive deteriorations, which impeded the return to work in one patient (9.1%). There were no differences with previous series regarding clinical, radiological, and molecular characteristics. Similar results were also found for functional, surgical, epileptical, and oncological outcomes. CONCLUSION: Although the right approach for iDLGG is still a matter of debate, our data support the safety and effectiveness of early surgical resection. More studies are needed to firmly ground this early "preventive" surgery approach.

Oncological, cognitive, and employment outcomes in a series of patients with IDH-mutated glioma resected following neoadjuvant chemotherapy.

PURPOSE: Maximal safe tumor resection is the first line of treatment for IDH-mutated gliomas. However, when upfront surgical resection is deemed unsatisfactory due to tumor size and location, chemotherapy could represent an interesting alternative for reducing glioma extension and allowing for a safer and more efficient removal. METHODS: We performed a retrospective study (June 2011 to December 2021) on patients with IDH-mutated gliomas undergoing chemotherapy with a neoadjuvant intent, followed by surgical excision in awake conditions. MRI-imaging follow-up was conducted every 3-6 months. Neuropsychological assessments (NPSA) were performed for all patients before surgery, during post-operative period, and at later follow-up, and patients were periodically interviewed about their clinical and job status. RESULTS: We included 6 patients who underwent awake surgery after neoadjuvant chemotherapy (temozolomide in 5 cases, PCV in 1 case) for an IDH-mutated glioma (3 oligodendrogliomas and 3 astrocytomas). Median tumor volume reduction was 47%, allowing for complete resection in one patient, subtotal resection in 4 patients, and partial resection in 1 patient. No major adverse effects were observed under chemotherapy. At the 4 months NPSA, a worsening of flexibility was observed in 2 patients (verbal fluencies in one case and trail making test in the other). Three out of the four patients working full time before procedure resumed their job full time, after a 7 to 10 months delay. CONCLUSION: Neoadjuvant chemotherapy followed by maximal safe resection can be offered to patients affected by IDH-mutated gliomas for whom upfront surgery would be inadequate. More studies are necessary given the limited size of our sample.

Nasal administration of recombinant Neospora caninum secreting IL-15/IL-15Rα inhibits metastatic melanoma development in lung.

BACKGROUND: Metastases are the leading cause of mortality in many cancer types and lungs are one of the most common sites of metastasis alongside the liver, brain, and bones. In melanoma, 85% of late-stage patients harbor lung metastases. A local administration could enhance the targeting of metastases while limiting the systemic cytotoxicity. Therefore, intranasal administration of immunotherapeutic agents seems to be a promising approach to preferentially target lung metastases and decrease their burden on cancer mortality. From observations that certain microorganisms induce an acute infection of the tumor microenvironment leading to a local reactivating immune response, microbial-mediated immunotherapy is a next-generation field of investigation in which immunotherapies are engineered to overcome immune surveillance and escape from microenvironmental cancer defenses. METHODS: The goal of our study is to evaluate the potential of the intranasal administration of Neospora caninum in a syngeneic C57BL6 mouse model of B16F10 melanoma lung metastases. It also compares the antitumoral properties of a wild-type N. caninum versus N. caninum secreting human interleukin (IL)-15 fused to the sushi domain of the IL-15 receptor α chain, a potent activator of cellular immune responses. RESULTS: The treatment of murine lung metastases by intranasal administration of an N. caninum engineered to secrete human IL-15 impairs lung metastases from further progression with only 0,08% of lung surface harboring metastases versus 4,4% in wild-type N. caninum treated mice and 36% in untreated mice. The control of tumor development is associated with a strong increase in numbers, within the lung, of natural killer cells, CD8+ T cells and macrophages, up to twofold, fivefold and sixfold, respectively. Analysis of expression levels of CD86 and CD206 on macrophages surface revealed a polarization of these macrophages towards an antitumoral M1 phenotype. CONCLUSION: Administration of IL-15/IL-15Rα-secreting N. caninum through intranasal administration, a non-invasive route, lend further support to N. caninum-demonstrated clear potential as an effective and safe immunotherapeutic approach for the treatment of metastatic solid cancers, whose existing therapeutic options are scarce. Combination of this armed protozoa with an intranasal route could reinforce the existing therapeutic arsenal against cancer and narrow the spectrum of incurable cancers.

DIMA-fr: a French adaptation and standardization of the Dutch Diagnostic Instrument for Mild Aphasia (DIMA-nl).

The Dutch Diagnostic Instrument for Mild Aphasia (DIMA-nl) is a standardized battery recently created for evaluating the language performance of patients during the perioperative period of glioma surgery. Our aim was to establish normative data for the DIMA-fr, a French version of the DIMA-nl. The DIMA-nl was first adapted to French. The 14 subtasks of the DIMA-fr were then administered to 391 participants recruited from the general French population. The effects of sex, age and level of education were determined by analysis of variance (ANOVA). Normative data were computed as means, medians, standard deviations and percentiles. Our results demonstrated that age and level of education had an effect on the performance of all subtests but not sex. We thus stratified the norms into four different groups: (i) 18-69 years-old with Baccalauréat (Bac, the French High School Diploma) (n = 246); (ii) 18-69 years-old without Bac (n = 70); (iii) >70 years-old with Bac (n = 48); (iv) >70 years-old without Bac (n = 27). The DIMA-fr is thus the first standardized French battery of tests to specifically assess language during the perioperative period of awake glioma surgery. However, to be used in the clinic, the DIMA-fr must now be validated in patients. The DIMA, which is currently standardized in several languages, could become a reference tool for international studies.

Group-level stability but individual variability of neurocognitive status after awake resections of right frontal IDH-mutated glioma.

Awake surgery for low-grade gliomas is currently considered the best procedure to improve the extent of resection and guarantee a "worth living life" for patients, meaning avoiding not only motor but also cognitive deficits. However, tumors located in the right hemisphere, especially in the right frontal lobe, are still rarely operated on in awake condition; one of the reasons possibly being that there is little information in the literature describing the rates and nature of long-lasting neuropsychological deficits following resection of right frontal glioma. To investigate long-term cognitive deficits after awake surgery in right frontal IDH-mutated glioma. We retrospectively analyzed a consecutive series of awake surgical resections between 2012 and 2020 for right frontal IDH-mutated glioma. We studied the patients' subjective complaints and objective neuropsychological evaluations, both before and after surgery. Our results were then put in perspective with the literature. Twenty surgical cases (including 5 cases of redo surgery) in eighteen patients (medium age: 42.5 [range 26-58]) were included in the study. The median preoperative volume was 37 cc; WHO grading was II, III and IV in 70%, 20%, and 10% of cases, respectively. Preoperatively, few patients had related subjective cognitive or behavioral impairment, while evaluations revealed mild deficits in 45% of cases, most often concerning executive functions, attention, working memory and speed processing. Immediate postoperative evaluations showed severe deficits of executive functions in 75% of cases but also attentional deficits (65%), spatial neglect (60%) and behavioral disturbances (apathy, aprosodia/amimia, emotional sensitivity, anosognosia). Four months after surgery, although psychometric z-scores were unchanged at the group level, individual evaluations showed a slight decrease of performance in 9/20 cases for at least one of the following domains: executive functions, speed processing, attention, semantic cognition, social cognition. Our results are generally consistent with those of the literature, confirming that the right frontal lobe is a highly eloquent area and suggesting the importance of operating these patients in awake conditions.

Immune response against toxoplasmosis-some recent updates RH: Toxoplasma gondii immune response.

AIMS: Cytokines, soluble mediators of immunity, are key factors of the innate and adaptive immune system. They are secreted from and interact with various types of immune cells to manipulate host body's immune cell physiology for a counter-attack on the foreign body. A study was designed to explore the mechanism of Toxoplasma gondii (T. gondii) resistance from host immune response. METHODS AND RESULTS: The published data on aspect of host (murine and human) immune response against T. gondii was taken from Google scholar and PubMed. Most relevant literature was included in this study. The basic mechanism of immune response starts from the interactions of antigens with host immune cells to trigger the production of cytokines (pro-inflammatory and anti-inflammatory) which then act by forming a cytokinome (network of cytokine). Their secretory equilibrium is essential for endowing resistance to the host against infectious diseases, particularly toxoplasmosis. A narrow balance lying between Th1, Th2, and Th17 cytokines (as demonstrated until now) is essential for the development of resistance against T. gondii as well as for the survival of host. Excessive production of pro-inflammatory cytokines leads to tissue damage resulting in the production of anti-inflammatory cytokines which enhances the proliferation of Toxoplasma. Stress and other infectious diseases (human immunodeficiency virus (HIV)) that weaken the host immunity particularly the cellular component, make the host susceptible to toxoplasmosis especially in pregnant women. CONCLUSION: The current review findings state that in vitro harvesting of IL12 from DCs, Np and MΦ upon exposure with T. gondii might be a source for therapeutic use in toxoplasmosis. Current review also suggests that therapeutic interventions leading to up-regulation/supplementation of SOCS-3, IL12, and IFNγ to the infected host could be a solution to sterile immunity against T. gondii infection. This would be of interest particularly in patients passing through immunosuppression owing to any reason like the ones receiving anti-cancer therapy, the ones undergoing immunosuppressive therapy for graft/transplantation, the ones suffering from immunodeficiency virus (HIV) or having AIDS. Another imortant suggestion is to launch the efforts for a vaccine based on GRA6Nt or other similar antigens of T. gondii as a probable tool to destroy tissue cysts.

Co-delivery of PLGA nanoparticles loaded with rSAG1 antigen and TLR ligands: An efficient vaccine against chronic toxoplasmosis.

Although vaccination is a promising approach for the control of toxoplasmosis, there is currently no commercially available human vaccine. Adjuvants such as delivery vehicles and immunomodulators are critical components of vaccine formulations. In this study, Poly (D, l-lactide-co-glycolide) (PLGA) nanoparticles were applied to serve as delivery system for both surface antigen-1 (SAG1), a candidate vaccine against toxoplasmosis and two TLR ligands, monophosphoryl lipid A (MPL) and imiquimod (IMQ), respectively. Compared to rSAG1 alone, CBA/J mice immunized with rSAG1-PLGA produced higher anti-SAG1 IgG antibodies titers. This response was increased by the co-administration of IMQ-PLGA (p < 0.01). Compared to IMQ-PLGA co-administration, MPL-PLGA co-administration further increased the humoral response (p < 0.01) and potentiated the Th1 humoral response. Compared to rSAG1 alone, rSAG1-PLGA, or rSAG1-PLGA mixed with IMQ-PLGA or MPL-PLGA similarly enhanced the cellular response characterized by the production of IFN-γ, IL-2, TNF-α and low levels of IL-5, indicating a Th1-biased immunity. The induced immune responses, led to significant brain cyst reductions (p < 0.01) after oral challenge with T. gondii cysts in mice immunized with either rSAG1-PLGA, rSAG1-PLGA + IMQ-PLGA, rSAG1-PLGA + MPL-PLGA formulations. Taken together the results indicated that PLGA nanoparticles could serve as a platform for dual-delivery of antigens and immunomodulators to provide efficacious vaccines against toxoplasmosis.

A Novel Calcium-Dependent Protein Kinase 1 Inhibitor Potently Prevents Toxoplasma gondii Transmission to Foetuses in Mouse.

Treatments currently used to prevent congenital toxoplasmosis are non-specific of Toxoplasma gondii and have grievous side effects. To develop a more specific and less toxic drug, we have designed SP230, an imidazo[1,2-b]pyridazine salt targeting the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) and active against acute toxoplasmosis in mice. Efficiency of SP230 to inhibit foetal transmission of the parasite was evaluated in a mouse model of congenital toxoplasmosis. Swiss mice were infected at mid-pregnancy with tachyzoites or cysts of the ME49 strain of T. gondii by intraperitoneal and oral route, respectively, and treated with SP230 at 50 mg/kg for 5 days by the same routes. Parasite burden in organs of dams and in foetuses was measured by quantitative PCR. Intraperitoneal administration of SP230 drastically reduced the number of parasites (more than 97% of reduction) in the brain and lungs of dams, and led to a reduction of 66% of parasite burden in foetuses. Oral administration of SP230 was particularly efficient with 97% of reduction of parasite burdens in foetuses. SP230 did not impact number and weight of offspring in our conditions. This inhibitor of TgCDPK1 is a promising candidate for the development of alternative therapeutics to treat infected pregnant women.

Neospora caninum glycosylphosphatidylinositols used as adjuvants modulate cellular immune responses induced in vitro by a nanoparticle-based vaccine.

Neospora caninum causes abortion in ruminants, leading to important economic losses and no efficient treatment or vaccine against neosporosis is available. Considering the complexity of the strategies developed by intracellular apicomplexan parasites to escape immune system, future vaccine formulations should associate the largest panel of antigens and adjuvants able to better stimulate immune responses than natural infection. A mucosal vaccine, constituted of di-palmitoyl phosphatidyl glycerol-loaded nanoparticles (DGNP) and total extract (TE) of soluble antigens of Toxoplasma gondii, has demonstrated its efficacy, decreasing drastically the parasite burden. Here, DGNP were loaded with N. caninum TE and glycosylphosphatidylinositol (GPI) of N. caninum as Toll-like receptor (TLR) adjuvant able to induce specific cellular and humoral immune responses. Activation of TLR2 and TLR4 signalling pathway in HEK reporter cells induced by GPI was abrogated after its incorporation into DGNP. However, in murine bone marrow-derived dendritic cells, an adjuvant effect of GPI was observed with higher levels of interleukin (IL)-1ß, reduced levels of IL-6, IL-12p40 and IL-10, and decreased expression of major histocompatibility complex (MHC) molecules. GPI also modulated the responses of bovine peripheral blood mononuclear cells, by increasing the production of IFN-γ and by decreasing the expression of MHC molecules. Altogether, these results suggest that GPI delivered by the DGNP might modulate cell responses through the activation of an intracellular pathway of signalisation in a TLR-independent manner. In vivo experiments are needed to confirm the potent adjuvant properties of N. caninum GPI in a vaccine strategy against neosporosis.

[Antitumoral microorganisms: The Swiss army knife of immunotherapy]. / Micro-organismes anti-cancéreux et armement - Le couteau suisse de l'immunothérapie.

Research on viruses, bacteria and protozoa-based immunotherapy has been on the rise for several years. The antitumoral efficacy of these microorganisms relies on three main mechanisms: Destruction of tumor cells, stimulation of the immune response and reprogramming of the tumor microenvironment. In order to optimize their immunotherapeutic action, these microorganisms can be genetically engineered to enhance their tumor-targeting efficacy or to vectorize immunostimulating molecules and/or antibodies. To this aim, molecular engineering allows the design of new antibody formats optimizing their functions. From whole antibodies to tandem single-chain variable fragments, various antibody formats can be vectorized by microorganisms to target receptors such as immune checkpoints or recruit immune effector cells within the tumor. Such possibilities broaden the arsenal of immunotherapeutic cancer treatment. This review focuses on these innovations and their advantages for immunotherapy.

TITLE: Micro-organismes anti-cancéreux et armement - Le couteau suisse de l'immunothérapie. ABSTRACT: Depuis plusieurs années, la recherche sur les micro-organismes pour une utilisation à des fins d'immunothérapie antitumorale est en plein essor. L'efficacité antitumorale de ces micro-organismes repose sur trois mécanismes principaux : la destruction des cellules tumorales, la stimulation du système immunitaire et la reprogrammation du microenvironnement tumoral. Afin d'optimiser leur action immunothérapeutique, ces micro-organismes peuvent être génétiquement modifiés pour les rendre capables de vectoriser des molécules immunostimulantes ou des anticorps. Par ingénierie moléculaire, il est désormais possible de diversifier les formats et fonctions de ces anticorps afin d'inhiber les points de contrôle immunitaire ou encore de recruter les cellules immunitaires effectrices au site de la tumeur. Cette Synthèse s'intéresse particulièrement à ces innovations et à leurs avantages en immunothérapie.

Key Limitations and New Insights Into the Toxoplasma gondii Parasite Stage Switching for Future Vaccine Development in Human, Livestock, and Cats.

Toxoplasmosis is a parasitic disease affecting human, livestock and cat. Prophylactic strategies would be ideal to prevent infection. In a One Health vaccination approach, the objectives would be the prevention of congenital disease in both women and livestock, prevention/reduction of T. gondii tissue cysts in food-producing animals; and oocyst shedding in cats. Over the last few years, an explosion of strategies for vaccine development, especially due to the development of genetic-engineering technologies has emerged. The field of vaccinology has been exploring safer vaccines by the generation of recombinant immunogenic proteins, naked DNA vaccines, and viral/bacterial recombinants vectors. These strategies based on single- or few antigens, are less efficacious than recombinant live-attenuated, mostly tachyzoite T. gondii vaccine candidates. Reflections on the development of an anti-Toxoplasma vaccine must focus not only on the appropriate route of administration, capable of inducing efficient immune response, but also on the choice of the antigen (s) of interest and the associated delivery systems. To answer these questions, the choice of the animal model is essential. If mice helped in understanding the protection mechanisms, the data obtained cannot be directly transposed to humans, livestock and cats. Moreover, effectiveness vaccines should elicit strong and protective humoral and cellular immune responses at both local and systemic levels against the different stages of the parasite. Finally, challenge protocols should use the oral route, major natural route of infection, either by feeding tissue cysts or oocysts from different T. gondii strains. Effective Toxoplasma vaccines depend on our understanding of the (1) protective host immune response during T. gondii invasion and infection in the different hosts, (2) manipulation and modulation of host immune response to ensure survival of the parasites able to evade and subvert host immunity, (3) molecular mechanisms that define specific stage development. This review presents an overview of the key limitations for the development of an effective vaccine and highlights the contributions made by recent studies on the mechanisms behind stage switching to offer interesting perspectives for vaccine development.

Neospora caninum: a new class of biopharmaceuticals in the therapeutic arsenal against cancer.

BACKGROUND: Microorganisms that can be used for their lytic activity against tumor cells as well as inducing or reactivating antitumor immune responses are a relevant part of the available immunotherapy strategies. Viruses, bacteria and even protozoa have been largely explored with success as effective human antitumor agents. To date, only one oncolytic virus-T-VEC-has been approved by the US Food and Drug Administration for use in biological cancer therapy in clinical trials. The goal of our study is to evaluate the potential of a livestock pathogen, the protozoan Neospora caninum, non-pathogenic in humans, as an effective and safe antitumorous agent. METHODS/RESULTS: We demonstrated that the treatment of murine thymoma EG7 by subcutaneous injection of N. caninum tachyzoites either in or remotely from the tumor strongly inhibits tumor development, and often causes their complete eradication. Analysis of immune responses showed that N. caninum had the ability to 1) lyze infected cancer cells, 2) reactivate the immunosuppressed immune cells and 3) activate the systemic immune system by generating a protective antitumor response dependent on natural killer cells, CD8-T cells and associated with a strong interferon (IFN)-γ secretion in the tumor microenvironment. Most importantly, we observed a total clearance of the injected agent in the treated animals: N. caninum exhibited strong anticancer effects without persisting in the organism of treated mice. We also established in vitro and an in vivo non-obese diabetic/severe combined immunodeficiency mouse model that N. caninum infected and induced a strong regression of human Merkel cell carcinoma. Finally, we engineered a N. caninum strain to secrete human interleukin (IL)-15, associated with the alpha-subunit of the IL-15 receptor thus strengthening the immuno-stimulatory properties of N. caninum. Indeed, this NC1-IL15hRec strain induced both proliferation of and IFN-γ secretion by human peripheral blood mononuclear cells, as well as improved efficacy in vivo in the EG7 tumor model. CONCLUSION: These results highlight N. caninum as a potential, extremely effective and non-toxic anticancer agent, capable of being engineered to either express at its surface or to secrete biodrugs. Our work has identified the broad clinical possibilities of using N. caninum as an oncolytic protozoan in human medicine.

Effective Nanoparticle-Based Nasal Vaccine Against Latent and Congenital Toxoplasmosis in Sheep.

Toxoplasma gondii is a parasitic protozoan of worldwide distribution, able to infect all warm-blooded animals, but particularly sheep. Primary infection in pregnant sheep leads to millions of abortions and significant economic losses for the livestock industry. Moreover, infected animals constitute the main parasitic reservoir for humans. Therefore, the development of a One-health vaccine seems the best prevention strategy. Following earlier work, a vaccine constituted of total extract of Toxoplasma gondii proteins (TE) associated with maltodextrin nanoparticles (DGNP) was developed in rodents. In this study we evaluated the ability of this vaccine candidate to protect against latent and congenital toxoplasmosis in sheep. After two immunizations by either intranasal or intradermal route, DGNP/TE vaccine generated specific Th1-cellular immune response, mediated by APC-secretion of IFN-γ and IL-12. Secretion of IL-10 appeared to regulate this Th1 response for intradermally vaccinated sheep but was absent in intranasally-vaccinated animals. Finally, protection against latent toxoplasmosis and transplacental transmission were explored. Intranasal vaccination led to a marked decrease of brain cysts compared with the non-vaccinated group. This DGNP/TE vaccine administered intranasally conferred a high level of protection against latent toxoplasmosis and its transplacental transmission in sheep, highlighting the potential for development of such a vaccine for studies in other species.

When Right Is on the Left (and Vice Versa): A Case Series of Glioma Patients with Reversed Lateralization of Cognitive Functions.

We report a case series of four patients operated on for a glioma in awake conditions and in whom task-based functional magnetic resonance imaging (fMRI) demonstrated right-dominant activity during a language production task. Language functional sites were identified intraoperatively by electrical stimulations only in the patient with a right-sided lesion. Furthermore, the pre- or postoperative cognitive evaluations in the three patients operated on for a left-sided glioma revealed right spatial neglect and dysexecutive syndrome, hence demonstrating that, in patients with right-dominant activity on language fMRI, the left hemisphere is implicated in spatial consciousness and cognitive control. This study supports the interest of presurgical task-based language fMRI to identify patients with a reversed lateralization of cognitive functions and to make an adequate selection of the battery of intraoperative cognitive tasks to be monitored in those rare outliers.

The challenge of overcoming the language barrier for brain tumor awake surgery in migrants: a feasibility study in five patient cases.

OBJECTIVE: To assess the feasibility of awake surgery for a brain tumor in a population of non-French-speaking migrants in Paris, France. METHODS: The Lariboisière database of awake surgeries was retrospectively reviewed, from the first case in 2011 up to July 2018. Inclusion criteria were patients being migrated in France during their adulthood, patients being unable to speak neither French nor English. Clinical and radiological data were collected from the electronic medical charts. RESULTS: Five patients fulfilled inclusion criteria. Pathological diagnosis included three glioma, one meningioma, and one melanoma metastasis. The standard awake protocol of our center was followed as usual, with the additional involvement of an interpreter at each step. In the five cases, the awake procedure allowed the surgeon to tailor the resection according to functional boundaries. Resections were complete in three cases and subtotal in two cases. No neurological deficits were observed. All patients returned to their preoperative socio-professional status. CONCLUSIONS: Awake surgery for a brain tumor can be offered to migrants, in spite of the poor verbal communication between the patient and the caring staff. A team dedicated to awake surgery and including an interpreter is the key to successfully overcome the language barrier, before, during, and after the surgery.

Babesia divergens glycosylphosphatidylinositols modulate blood coagulation and induce Th2-biased cytokine profiles in antigen presenting cells.

Glycosylphosphatidylinositols (GPIs) are glycolipids described as toxins of protozoan parasites due to their inflammatory properties in mammalian hosts characterized by the production of interleukin (IL)-1, IL-12 and tumor necrosis factor (TNF)-α. In the present work, we studied the cytokines produced by antigen presenting cells in response to ten different GPI species extracted from Babesia divergens, responsible for babesiosis. Interestingly, B. divergens GPIs induced the production of anti-inflammatory cytokines (IL-2, IL-5) and of the regulatory cytokine IL-10 by macrophages and dendritic cells. In contrast to all protozoan GPIs studied until now, GPIs from B. divergens did not stimulate the production of TNF-α and IL-12, leading to a unique Th1/Th2 profile. Analysis of the carbohydrate composition of the B. divergens GPIs indicated that the di-mannose structure was different from the evolutionary conserved tri-mannose structure, which might explain the particular cytokine profile they induce. Expression of major histocompatibility complex (MHC) molecules on dendritic cells and apoptosis of mouse peritoneal cells were also analysed. B. divergens GPIs did not change expression of MHC class I, but decreased expression of MHC class II at the cell surface, while GPIs slightly increased the percentages of apoptotic cells. During pathogenesis of babesiosis, the inflammation-coagulation auto-amplification loop can lead to thrombosis and the effect of GPIs on coagulation parameters was investigated. Incubation of B. divergens GPIs with rat plasma ex vivo led to increase of fibrinogen levels and to prolonged activated partial thromboplastin time, suggesting a direct modulation of the extrinsic coagulation pathway by GPIs.